U.S. patent application number 12/532486 was filed with the patent office on 2011-03-03 for implant material based on a polymer system and the use thereof.
This patent application is currently assigned to INNOTERE GMBH. Invention is credited to Berthold Nies.
Application Number | 20110054392 12/532486 |
Document ID | / |
Family ID | 39560938 |
Filed Date | 2011-03-03 |
United States Patent
Application |
20110054392 |
Kind Code |
A1 |
Nies; Berthold |
March 3, 2011 |
Implant Material Based On A Polymer System And The Use Thereof
Abstract
An implant material on the basis of a polymer system has a first
component and a second component that react with one another when
mixed to form a polymer-based solid. The first component is a paste
that contains at least one biocompatible polymer powder and a
starter component for initiating a polymerization reaction upon
mixing, wherein the paste has a carrier liquid, wherein under
normal conditions in the carrier liquid the at least one
biocompatible polymer powder does not dissolve or significantly
swell and the starter component remains stable until mixing with
the second component of the polymer system. The second component of
the polymer system contains at least one reactive organic liquid or
a solution or a suspension of a reactive organic liquid and of a
polymer.
Inventors: |
Nies; Berthold;
(Fraenkisch-Crumbach, DE) |
Assignee: |
INNOTERE GMBH
Dresden
DE
|
Family ID: |
39560938 |
Appl. No.: |
12/532486 |
Filed: |
March 27, 2008 |
PCT Filed: |
March 27, 2008 |
PCT NO: |
PCT/EP2008/053640 |
371 Date: |
September 22, 2009 |
Current U.S.
Class: |
604/82 ;
514/772.3; 523/115; 523/116; 977/700 |
Current CPC
Class: |
A61P 19/08 20180101;
A61L 24/0036 20130101; A61L 24/0042 20130101; A61L 27/58 20130101;
A61L 24/0073 20130101; A61L 27/44 20130101; A61P 19/10 20180101;
A61L 27/56 20130101 |
Class at
Publication: |
604/82 ; 523/115;
523/116; 514/772.3; 977/700 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61F 2/28 20060101 A61F002/28; A61L 24/04 20060101
A61L024/04; A61K 47/30 20060101 A61K047/30 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 27, 2007 |
DE |
10 2007 015 698.9 |
Claims
1.-23. (canceled)
24. An implant material on the basis of a polymer system
comprising: a first component and a second component that react
with one another when mixed to form a polymer-based solid; wherein
the first component of the polymer system is a paste that contains
at least one biocompatible polymer powder and a starter component
for initiating a polymerization reaction upon mixing, wherein the
paste comprises a carrier liquid, wherein under normal conditions
in the carrier liquid the at least one biocompatible polymer powder
does not dissolve or significantly swell and the starter component
remains stable until mixing with the second component of the
polymer system; and wherein the second component of the polymer
system contains at least one reactive organic liquid or a solution
or a suspension of a reactive organic liquid and of a polymer.
25. The implant material according to claim 24, wherein the at
least one biocompatible polymer is selected from homopolymers or
copolymers of acrylic acid esters, methacrylic acid esters, styrene
derivatives, vinyl derivatives or their mixtures.
26. The implant material according to claim 24, wherein the carrier
liquid is selected from water, aqueous solutions, glycerin,
glycerin esters, propane diol, low-molecular PEG, PEG-PPG
copolymers, DMSO, methyl pyrrolidone, biocompatible oils, or their
mixtures with one another or their mixtures with one another and
with other substances.
27. The implant material according to claim 24, wherein the second
component contains as a reactive organic liquid methylmethacrylate
or homologue esters of methacrylic acid or their mixtures.
28. The implant material according to claim 24, wherein the polymer
of the second component is a polyacrylic acid ester or a
polymethacrylic acid ester or a polystyrene or their copolymer.
29. The implant material according to claim 24, wherein the first
and second components of the polymer system contain a starter
system of a two-component radical starter, comprising the starter
component that is present in the first component of the polymer
system and a second radical starter component with a co-starter,
polymerization accelerator or initiator, wherein the starter
component is present in the first component of the polymer system
in undissolved form and the second radical starter component is
contained in the second component of the polymer system.
30. The implant material according to claim 29, wherein the starter
component is a peroxide and the second radical starter component is
a tertiary amine.
31. The implant material according to claim 24, wherein the first
component or the second or both the first and second components of
the polymer system contain auxiliary agents or active ingredients
or both auxiliary agents and active ingredients.
32. The implant material according to claim 24, wherein the carrier
liquid of the first component of the polymer system and the
reactive organic liquid of the second component of the polymer
system are immiscible with one another or not or only minimally
soluble in one another and upon mixing the first and second
components substantially a physical mixture results.
33. The implant material according to claim 32, wherein at least
one of the first and second components of the polymer system
contains at least one biocompatible surface-active agent that
assists in forming a physical mixture of the first and second
components.
34. The implant material according to claim 32, wherein at least
one of the first and second components of the polymer system
contains at least one biocompatible surface-active agent selected
from an anionic surface-active agent and a non-ionic surface-active
agent.
35. The implant material according to claim 32, wherein at least
one of the first and second components of the polymer system
contains at least one biocompatible anionic surface-active agent
and at least one of the first and second components of the polymer
system contains a non-ionic surface-active agent or a
co-surfactant.
36. The implant material according to claim 32, wherein at least
one of the carrier liquid of the first component and the reactive
organic liquid of the second component of the polymer system
contains water-soluble monomers or water-soluble macromers that can
polymerize during or after polymerization of the polymer system
within an aqueous phase of the polymer-based solid that is being
formed.
37. The implant material according to claim 36, wherein the
water-soluble monomers are selected from methacrylic acid, HEMA,
HPMA, HEMA phosphate, sulfopropyl methacrylate, their homologues or
their mixtures.
38. The implant material according to claim 36, wherein the
water-soluble macromers are selected from PEG-mono-acrylate,
PEG-di-methacrylate, branched PEG-n-methacrylates, their homologues
or their mixtures.
39. The implant material according to claim 24, wherein the first
and second components of the polymer system contain dissolved
polymers or finely divided suspended organic, inorganic or
organo-mineral components for adjusting a viscosity of the first
and second components of the polymer system, wherein the viscosity
of the first and second components of the polymer system does not
surpass the value of 200 Pa*s.
40. The implant material according to claim 24, wherein at least
one of the first and second components of the polymer system
contains microcrystalline, nanocrystalline or amorphous bone
minerals or synthetic bone-analog minerals.
41. The implant material according to claim 24, wherein at least
one of the first and second components of the polymer system
contains at least one biocompatible substance that serves as a
crystallization seed for mineral depositions, enhances the
formation of mineral depositions, or serves as a crystallization
seed for mineral depositions and enhances the formation of mineral
depositions, wherein the at least one biocompatible substance
contains at least one carboxyl, sulfate, and/or phosphate group
and/or a siloxane group.
42. The implant material according to claim 24, wherein the
polymer-based solid that is being formed in the course of
polymerization has a porosity of more than 10%.
43. The implant material according to claim 42, wherein the
polymer-based solid has an interconnected pore system.
44. The implant material according to claim 24 in the form of bone
cements, bone replacement materials, bone adhesives, and
implantable active ingredient carriers.
45. An application kit comprising: an implant material according to
claim 24; a double chamber syringe and a forced mixer/static mixer
or components connectable to form a double chamber syringe and
combinable with a forced mixer/static mixer.
46. A combination of an implant material according to claim 24 with
application systems for augmentation of osteoporotic or other
pathologically changed bone areas and for filling bone defects of
any kind.
Description
[0001] The invention concerns an implant material based on a
polymer system of at least two components and its use as a bone
cement, bone adhesive, bone replacement material or active
ingredient carrier.
[0002] Polymer-based bone cements are clinically used primarily for
attachment of joint implants. They have been established for
approximately 50 years in clinical practice and today are used
worldwide in approximately 5 million cases. The chemical
composition of the bone cements has practically remained unchanged
during this time. It is comprised substantially of a powder
component that contains one or several polymers, primarily
comprised of acrylates, methacrylates, and styrene, or copolymers
of these monomers or mixtures of the corresponding homopolymers
and/or copolymers (referred to summarily as PMMA). Further
components of the powder component are in general an x-ray contrast
agent and a radical starter. As an x-ray contrast agent preferably
barium sulfate or zirconium dioxide are used. As a radical starter
in all commercially available bone cements dibenzoyl peroxide (BPO)
is used. The second bone cement component is a reactive organic
liquid that is quite predominantly comprised of the monomer methyl
acrylate (MMA) and, in rare cases, also contains other esters of
acrylic acid or methacrylic acid. Further components are a
co-starter (also referred to as activator or co-initiator) and a
stabilizer or inhibitor. As a co-starter in almost all commercial
bone cements dimethyl-p-toluidine (DMPT) is used, very rarely
another tertiary amine. As inhibitor primarily hydroquinone or one
of its derivatives is employed.
[0003] In addition, bone cements can also contain further
substances (antibiotics, coloring agents) that in the present
context will however initially not be considered.
[0004] When in a conventional bone cement powder and liquid are
mixed with one another, the initiator (BPO) and co-starter (DMPT)
react with one another under formation of radicals that, in turn,
attack the double bonds of the monomer molecules and trigger a
polymerization (chain) reaction until the predominant portion of
the monomer has reacted to polymer chains. Parallel to this, the
monomer solubilizes or dissolves a portion of the polymer which
initially may lead to a fast increase of viscosity of the cement
material and which causes an intimate connection of powder and
polymerizing liquid. The complete curing reaction from the mixture
to the full loading capacity is completed in conventional PMMA bone
cement in approximately 10-30 minutes. PMMA bone cements, despite
the long experience and the wide use, have a series of
disadvantages: [0005] Mixing: the cement powder is a mixture of
very fine powders that, in turn, have very different properties
(particle size, density differences of 1.18 for PMMA and 5.85 for
ZrO.sub.2) and therefore are difficult to be homogeneously mixed
and therefore require corresponding manufacturing expenditure.
Mixing of the cement powder with the monomer liquid also
constitutes a problem because the viscosity of the liquid increases
very quickly and then a homogenous mixing is made difficult. A
substantially pore-free cement material is practically achieved
only by using complex and expensive mixing systems. [0006]
Shrinkage: during the polymerization reaction the density upon
passing from pure monomer to polymer increases by more than 20% and
the volume decreases correspondingly. Since the bone cement largely
contains already polymerized material (PMMA proportion), in this
system the shrinkage is significantly lower and is indicated to be
approximately 2-5% (Kuhn, Bone Cements, Springer Verlag, 2000, ISBN
3-540-67207-9). Aside from the high polymerization heat, the
shrinkage can be considered a significant clinically relevant
disadvantage of conventional bone cements that limits the
application possibilities with respect to important clinical
indications. In case of required great layer thicknesses (as, for
example, when replacing a prosthesis) the shrinkage can cause the
formation of a distinct gap between cement and bone so that a
physiological force transmission is no longer possible. [0007]
Polymerization heat: the polymerization reaction of MMA to PMMA is
greatly exothermic. The obtained peak temperatures according to ISO
5833 are at approximately 80.degree. C. and depend quite
considerably on the quantity ratio of monomer to total cement
weight and to a lesser degree on the polymerization kinetics.
Clinically relevant is the high polymerization heat in particular
for large quantities of cement to be applied when the surrounding
tissue cannot remove fast enough the generated heat in order to
avoid tissue necrosis. [0008] Mechanics: for most of the
applications customary today PMMA bone cement has satisfactory
mechanical properties. For some new applications--in particular,
vertebroplastics or generally stiffening of spongy bone--the high
stiffness is however often considered a disadvantage. A reduced
stiffness may provide clinical advantages in many fields of
application, even the traditional ones. [0009] Active ingredient
release: the majority of bone cement applications is focused today
in many countries on the antibiotics-containing versions for
prophylaxis of foreign body-associated infections. In order to
achieve satisfactory release, very high doses must be mixed into
the cement of which the predominant part is released over a very
long period of time in very low concentrations (or not at all).
This fact is often linked with the development and spread of
resistant bacteria strains. Obtaining satisfactory effective levels
at much lower dosages that may be released completely over a
shorter period of time is therefore desirable. [0010] Tissue
compatibility: PMMA is tissue-compatible to a satisfactory extent
and fulfills the standardized requirements with respect to
biocompatibility of implant materials. PMMA however is not
integrated into the bone but is encapsulated by scar tissue. This
has biochemical causes as well as structural reasons. Solid bone
cement provides to the surrounding bone no possibility to grow into
an external pore system and to thus achieve a secondary
interlocking as is the case in modern uncemented permanent metal
implants.
[0011] WO 2005/009481 A1 discloses a bone cement containing a
surface-active agent and comprised of a liquid component and a
solid component. The powder component is unchanged relative to
conventional bone cement; only the liquid component contains in
addition to the monomer a surface-active ingredient and an
accelerator. Immediately before use the components are mixed. The
goal of WO 2005/009481 A1 is to impart to a conventional bone
cement an improved release of antibiotic agents.
[0012] WO 2004/071543 A1 discloses an injectable bone replacement
mixture of a) a two-component powder liquid bone cement, b) a
further component that is not miscible with the cement paste, and
c) an x-ray contrast agent. After mixing the components a
self-curing porous bone replacement material is said to be formed
in which component b after curing can be washed out. The teaching
of WO 2004/071543 A1 is limited to a conventional powder liquid
system to which, only after mixing the conventional components has
been done, an immiscible liquid for pore formation is added.
[0013] DE 32 45 956 A1 concerns a surgical material on the basis of
liquid monomer and powdery polymer acrylic acid esters and/or
methacrylic acid esters, catalysts, accelerators, and optionally
additives, in which the liquid component is not an aqueous emulsion
but a solution with special organic liquids that do not participate
in the polymerization reaction and that lead to a reduced heat
development upon mixture and incorporation of the surgical
material.
[0014] U.S. Pat. No. 4,093,576 discloses a bone cement mixture of a
polymer powder and a highly viscous water-soluble gel of more than
200,000 centipoise that is compatible therewith. Upon mixing these
components a porous bone replacement material is produced.
[0015] The object of DE 10 2004 049 A1 is an antibiotic-containing
or antibiotics-containing PMMA bone cement with a powder component
and a liquid component. In this connection, as a result of the
specific composition of the added antibiotics their release is said
to be significantly increased.
[0016] Cement-type compositions that are comprised of two pastes
and are offered in double chamber syringes and are combined and
reacted by means of static mixers have been known primarily from
dental practice for quite some time. A product derived therefrom
(Cortoss of the Orthovita company) has been developed in recent
years also for the field of orthopedics. The dental filling
materials as well as the product Cortoss differ significantly from
the conventional bone cements as a result of their proportion of
glass-ceramic filler materials in the first paste. As a starter
system BPO/DMPT is employed wherein DMPT is contained in the first
paste and BPO is present in dissolved form in the second paste and
is stable with regard to storage only by cooling. A satisfactory
storage stability is ensured for this product only for continuous
cooling and the mineral fillers that are added in high
concentration have the tendency, despite the high viscosities, to
form sediments. The implant material according to the present
invention is significantly distinguished from the products such as
Cortoss and dental filling materials in that the materials
according to the present invention always contain a suspension of
polymer powders in carrier liquids in which they are neither
soluble nor swellable to a significant extent. Furthermore, there
is a significant material differentiation in that the products such
as Cortoss in both cement components contain as monomers primarily
macromers with more than one double bond while the monomer liquid
in the materials according to the present invention predominantly
are comprised of the monovalent MMA and polymers dissolved
therein.
[0017] In recent years publications in regard to two-paste PMMA
cements have also been published in scientific literature which are
based on conventional bone cements (Li et al., Bioactive and
osteoporotic bone cement, U.S. Pat. No. 6,593,394 B1: Gilbert J L,
Hasenwinkel J M, Wixson R L, Lautenschlager E P, J. Biomed, Mater.
Res. 2000 October 52(1):210-218). These cases concern exclusively
highly viscous solutions of PMMA copolymers in MMA with high
contents of mineral filler materials in which one paste contains
the BPO and the other one the DMPT. These compositions have thus
the same technological disadvantages as Cortoss with regard to
storage stability and sedimentation. Also disadvantageous in this
connection is the very high heat development during polymerization
that is caused by the necessary high MMA contents for the paste
preparation.
[0018] In the early '80s of the 20th century the company Beiersdorf
developed a bone cement and introduced it into the market which
bone cement contains in the powder component a conventional
composition but as a monomer liquid contains an emulsion of
approximately 10% water in MMA. The goal was primarily lowering of
the polymerization temperature. With the exception of use of
emulsifying agents and aqueous components in the overall
formulation there are no principal commonalities with the
composition according to the present invention.
[0019] Inspired by clinical problems in connection with demands on
bone cements for vertebroplastics, in recent years a series of
tests for blending bone cements with aqueous polymer solutions, in
particular hyaluronic acid, have been performed in order to reduce
the stiffness of the cements.
[0020] According to Boger A., Verrier S., Bohner M., Heini P.,
Schneider E.--Injizierbarer poreser Knochenzement fur die
Vertebroplastik mit physiologisch angepassten mechanischen
Eigenschaften (Injectable porous bone cement for vertebroplastics
with physiologically matched mechanical properties), Bern; DGU,
2005--conventional bone cements were first mixed and subsequently
hyaluronic acid was admixed. This procedure leads in contrast to
the method according to the invention to results that are hardly
reproducible and causes dramatic strength losses already for
relatively low quantities of hyaluronic acid. The fundamental
reason for the unsatisfactory results is linked to the practically
unachievable uniform dispersion of aqueous solutions in an already
premixed bone cement paste under conditions in the operating room
and with means that are available therein. The obtained cement
materials are correspondingly inhomogeneous so that this method is
impractical for clinical use. The cited works are therefore in no
way an anticipation of the actual invention since neither the
concrete teaching is disclosed nor the obtained results are
achieved.
[0021] As a whole, the aforementioned works shows that there is an
acute interest in an improvement of conventional bone cements and
that the solutions that have been presented in the past are still
far removed from a satisfactory solution.
[0022] The present invention ties in with the weak points of
conventional PMMA bone cements in that it follows a new approach
for preparation and material composition of bone cements while it
is still based on the established starting materials. In this way,
implant materials, in particular for bone cements, for
vertebroplastics and filling of bone defects in the context of
prosthesis revision and for the augmentation of osteoporotic bones
are to be provided but also materials for non-medical fields of
applications are to be developed.
[0023] According to the present invention, the object is solved by
an implant material with the features according to claim 1. Further
embodiments and applications of this implant material are contained
in claims 2 to 22.
[0024] The implant material according to the present invention on
the basis of a biocompatible polymer system is comprised of at
least two components that upon being mixed with one another react
with one another and form a polymer-based solid wherein at least
the first component of the polymer system is a paste of at least
one biocompatible polymer and a starter component or a starter for
initiating a polymer reaction upon mixing.
[0025] According to the invention the first component of the
polymer system is a storage-stable paste of at least one
biocompatible polymer powder and a starter component or a starter
and a carrier liquid wherein the carrier liquid is selected such
that under normal conditions the polymer powder will not dissolve
or swell significantly and the starter component remains stable up
to the point of mixing the components of the polymer system.
[0026] The second component of the polymer system contains at least
one reactive organic liquid or a solution or a suspension of a
reactive organic liquid and a polymer.
[0027] According to the invention the first component of the
polymer system is embodied as a paste wherein the composition of
this paste preferably is rooted in the composition of the powder
component of conventional bone cements, i.e., contains polymer
powder and radical starter (preferably BPO) and optionally x-ray
contrast agents and optionally active ingredients. These components
are combined with the carrier liquid such that the polymer powder
and the starter component do not dissolve in the carrier liquid but
are suspended therein. The suspension in the inventive form is
present as a paste. Pastes are by definition suspensions of solids
in liquids with a high solid contents. Pastes are usually not
flowable but easily deformable. In the context of this invention
the term paste is used as a descriptive term because an exact
limitation based on viscosities is not available. Accordingly,
pastes are to be understood as semi-solid materials that
approximately cover the ranges that are also conventional with
respect to toothpaste. The term paste however is to be understood
to serve solely for differentiating the first component of the
polymer system from the powdery, granular or other solid
materials.
[0028] The gist of the invention is the novel formulation of the
powder component of bone cements that are composed substantially of
conventional materials as they are disclosed e.g. in Kuhn, Bone
Cements, Springer Verlag, 2000. For this purpose, the conventional
powder components, polymer powder, x-ray contrast agent (if
contained) and starter components and optionally further additives
are formulated as a paste or suspension in a carrier liquid in
which these components (in particular the starter component) are
stable under normal conditions. Normal conditions are defined as
25` C and 101.3 kPa.
[0029] The biocompatible polymer powder of the first component of
the polymer system is selected from homopolymers or copolymers of
acrylic acid esters, methacrylic acid esters, styrene derivatives,
vinyl derivatives or their mixtures.
[0030] The implant material according to the invention on the basis
of a self-curing/cold curing polymer system is based in a preferred
embodiment on commercially available bone cements and their product
specifications in order to tie into the long-standing experiences
with these materials. A comprehensive overview of this product
group is disclosed in the monograph Bone Cement (Kuhn, Springer
Verlag, 2000, ISBN 3-540-67207-9). The technology according to the
invention makes available for the first time the possibility to go
beyond the boundaries of prior bone cements with respect to
composition and the property spectrum that can be achieved by the
powder/liquid systems.
[0031] The selection of suitable polymers is exclusively based on
their compatibility with the monomers systems to be used in
accordance with the invention. The compatibility of polymers with
one another is greatly influenced and limited by their chemical
structure. This fact impairs, on the one hand, the selection
possibilities for development and production of polymer blends but,
on the other hand, it is also used in a targeted fashion in order
to influence by separation processes and targeted incorporation of
inhomogeneities the mechanical properties, the breaking behavior,
tribological properties or other surface properties. Even when in
the present invention with respect to the preferred use of the
materials as a bone cement polymer systems on the basis of
homopolymers or copolymers of acrylic acid esters and/or
methacrylic acid esters, styrene derivatives, vinyl derivatives
and/or their mixtures are the primary focus, in this context
expressly all polymers are suitable and claimed that can be
solubilized or dissolved in the polymerizable monomers and
macromers or that can be fixedly bonded in a matrix of
polymerizable monomers or monomer solutions.
[0032] For producing the first component as a paste at least one
polymer (powder) and one starter (that may already be contained in
the polymer) are suspended in a carrier liquid. The carrier liquid
is preferably water or an aqueous solution (however, as mentioned
above, in principle all other liquids can be taken into
consideration that neither serve as a solvent for the starter nor
the polymer). With respect to the preferred application as a bone
cement biocompatible liquids that are established as pharmaceutical
adjuvants are particularly preferred, in particular in addition to
water and aqueous solutions, glycerin, glycerin ester, propane
diol, low-molecular PEG, PEG-PPG-copolymers, DMSO, methyl
pyrrolidone, biocompatible oils, their mixtures with one another
and with other substances.
[0033] As a starter component or starter preferably a peroxide,
preferably BPO, is used. The use of BPO in conventional bone
cements has been established practice for decades. In these cases
the BPO is present in the powder component and is phlegmatized with
water (in special cases, the BPO is polymerized into the polymer
component which also effects phlegmatization). In phlegmatized form
the BPO is storage-stable for an extended period of
time--commercially available bone cements have a storage stability
of up to 5 years.
[0034] In commercially available two-component paste systems
(Cortoss or other filler materials) the BPO is present in one of
the components in dissolved form. In this form, the BPO is not
phlegmatized and decomposes spontaneously as a function of
temperature. The stability of BPO limits therefore the storage
stability of this product. For increasing the storage stability the
corresponding products must therefore be cooled which is
undesirable for reasons of logistics.
[0035] In the implant material according to the invention the
starter component in the carrier liquid is present in undissolved
form. When using peroxide, the peroxide is preferably BPO as in
conventional bone cements, preferably phlegmatized with water.
Therefore, there are no disadvantageous effects with respect to
storage stability.
[0036] As a carrier liquid all biocompatible liquids are possible
in which the starter component is stable and in which the polymer
powder will not dissolve or will not swell significantly (<5%).
Especially preferred are water and aqueous solutions, glycerin,
glycerin esters, propane diol, low-molecular PEG, PEG-PPG
copolymer, DMSO, methyl pyrrolidone, biocompatible oils, their
mixtures with one another and with other substances. The carrier
liquid can have mixed in various substances that have the function,
on the one hand, to suspend the powder components effectively in
the liquid and, on the other hand, to influence the biological,
mechanical, and structural properties of the bone cement.
[0037] The second component of the polymer system contains at least
one reactive organic liquid or a solution or a suspension of a
reactive organic liquid and a polymer. The reactive organic liquid
is selected in this connection from methyl methacrylate or
homologue esters of methacrylic acid or their mixtures.
[0038] The second component of the polymer system according to the
invention is less strongly modified relative to conventional bone
cements. Modifications relate here substantially to measures for
affecting the viscosity and the wetting behavior so that both
components are matched to one another and can be mixed with one
another easily in the desired way.
[0039] The goal of this adjustment may reside, on the one hand, in
that both components can be homogeneously mixed with one another
and, on the other hand, in that during mixing predetermined and
controlled inhomogeneities will occur. In the first case,
the--modified--monomer liquid and the carrier liquid of the paste
or of the powder suspension can be mixed with one another so that a
molecular distribution without formation of phase boundaries
between the employed liquids will result. In this case, the type
and manner of polymerization corresponds to a solvent
polymerization in which the solvent after completion of
polymerization either remains permanently in the cement material or
is later on partially or completely released into the surrounding
medium. In the second and preferred case the first and second
components of the polymer system (paste or powder suspension
and--modified--monomer liquid) upon mixing form a physical mixture
in the sense of an emulsion in which the carrier liquid of the
paste and the monomer liquid form separate phases. These physical
mixtures are favored by the use of suitable emulsifying
agents/surface-active agents or their mixtures and, if required,
are assisted by stabilizers and are stabilized at least for the
duration of the mixing step up to the termination of the
polymerization reaction. In this case, the type and manner of
polymerization corresponds to a suspension or emulsion
polymerization in which, after intimate mixing of the two
components, the--modified--monomer liquid and components of the
powder paste form the continuous phase, while the suspended phase
is substantially formed of the carrier liquid of the original
powder paste. The actual polymerization takes place in this case
practically exclusively in the continuous phase. Both components
can be matched to one another such that the suspended phase forms
isolated droplets or liquid-filled pores in the polymerized
continuous phase or that the suspended phase forms an
interpenetrating network with the continuous phase, i.e., a
substantially interconnected pore system communicating with the
external medium.
[0040] Experiments have surprisingly shown that from the powder
component of conventional bone cements (e.g. Palacos.RTM. of the
companies Biomet-Merck or Heraus Medical), an aqueous polymer
solution (e.g. carboxy methyl starch), and a suitable biocompatible
surface-active agent (e.g. Tween.RTM. 80) storage-stable pastes can
be produced. These pastes can be mixed excellently with a
conventional monomer solution (e.g. MMA solution for Palacos.RTM.
of the company Biomet-Merck or Heraus Medical) in which minimal
quantities of PMMA-PMA copolymer (e.g. Degacryl.RTM. of the company
Degussa) are dissolved, wherein upon complete mixing within a short
period of time a macroscopic, homogenous emulsion is formed that
also within a short period of time (<10 min.) spontaneously
polymerizes and forms a solid porous cement material.
[0041] The predetermined selection whether during the course of the
curing reaction a solid or porous structure is formed, can be
achieved in particular by selection of the carrier liquid of the
first component of the polymer system. When the carrier liquid of
the first component is miscible with the monomer liquid of the
second component of the polymer system, one obtains primarily a
solid material while the use of a carrier liquid that is not
miscible with the monomer liquid produces a porous solid. In
differentiating both cases, the term of miscibility is important.
For complete miscibility or chemical mixtures the mixed substances
are present in molecular distribution, i.e., the mixtures are
homogenous up to molecular range and there are no phase boundaries
between the mixed substances. Examples are solutions of substances
within one another. In the present case, this applies to propane
diol as a carrier liquid that is miscible with the MMA monomer. The
polymerization then forms a solid material that is almost
pore-free. The introduced propane diol after polymerization is
(molecularly) distributed in the polymer matrix.
[0042] When no or no complete miscibility of the substance is
present, phase boundaries between the substances are formed in that
the suspensions (solid in liquid) or emulsions (liquid in liquid)
can form. In the present case this applies when the carrier liquid
of the first component of the polymer system and the monomer liquid
are not completely miscible with one another. The preferred case is
the use of an aqueous solution as a carrier liquid of the first
component of the polymer system and a PMMA copolymer solution in
MMA as a second component of the polymer system. MMA is only
slightly soluble in water and therefore upon mixing of the two
components no homogenous chemical mixture can be formed. The
surface tension of the two liquids and their polarity differences
effect a separation that however can be controlled by use of
suitable surface-active substances (surfactants). Mixing of the two
components of the polymer system has in this case the result that
the suspended polymer powder of the first component--because of the
similar polarity--will combine with the MMA liquid and the BPO
(also suspended in the first component) also passes into the MMA
because of its excellent solubility in MMA. In the MMA phase the
polymerization can then take place because now BPO and DMPT are
both present in the same phase and can react with one another. The
presence of the polymer powder and of the surface-active agents
combined with the increased viscosity of both components prevents a
complete coalescence of the two phases and leads to formation of a
contiguous pore system in which the aqueous solution of the carrier
liquid fills the pore system.
[0043] In this context the following items are particularly
surprising: [0044] Mixing of conventional bone cement powder, an
aqueous polymer solution, and biocompatible surface-active agents
provides a storage-stable paste with macroscopic homogeneity and
excellent handling properties, e.g., very high solid contents can
be adjusted while at the same time extrudability by means of
commercially available syringes is maintained. Sedimentation of
components of the powder component, in particular of zirconium
dioxide, was not observed. [0045] The paste can be easily mixed
with a conventional monomer that is matched with regard to
viscosity in a simple mixing cup or in a generally known double
chamber syringe (in the present case of the company Mixpac.RTM.,
Switzerland) so that a macroscopically homogeneous cement material
results. Even without special measures for open mixing no
macropores are introduced into the cement material as is the case
regularly in powder/liquid mixtures. [0046] In the mixture
according to the invention the polymerization reaction of the
formulation that is based on the formulation of conventional bone
cement (Palacos.RTM.) is significantly faster than in the
comparable formulation in powder/liquid mixtures. [0047] Especially
surprising is the broad spectrum of mixing ratios between both
components of the formulation according to the invention within
which cement reactions with promising properties will occur. In
particular, the powder pastes can be mixed with very much smaller
quantities of monomer liquid than can be achieved with the
powder/liquid mixtures. [0048] The exothermicity can be reduced
significantly as a function of the monomer quantity. [0049] Despite
the microporous structures of the cured cement surprisingly high
strengths can be achieved. [0050] The micropores form depending on
the adjustment of the cement formulation according to the present
invention an interconnected pore system. This property could not be
obtained up to now for any self-curing implant material that has an
appreciable structural strength.
[0051] Characteristic for the present invention is the realization
of a self-curing polymer system that is comprised of at least two
components wherein a first component contains a dispersion or
suspension of polymer in a carrier liquid and this carrier liquid
cannot dissolve the polymer nor can it cause a significant swelling
of the polymer in the carrier liquid. In this connection, as a
carrier liquid practically all liquids can be considered in which
polymers that are suitable for producing self-curing plastic
systems are stable. A further characteristic and prerequisite is
that the starter system is compatible with the carrier liquid. In
this regard, the invention differs fundamentally from known
two-paste systems that throughout contain either multi-valent
cross-linkable macromers or solutions of polymers in low-molecular,
usually mono-valent, monomers. Starter and co-starter or initiator
each are dissolved in one of the separated pastes and are reacted
upon mixing the pastes so that the polymerization is initiated.
Usually, these two-paste systems also contain various non-reactive
fillers.
[0052] Important components of the carrier liquid are substances
that improve the dispersibility of the polymer. Of great importance
are moreover substances that can be used for adjusting the
viscosity of the carrier liquid. These include in particular
polymers which are dissolvable in the carrier liquid and/or viscous
liquids that are miscible with the carrier liquid. Moreover,
substances are included that can modify as very fine dispersions
the viscosity and rheology of liquids, as in particular highly
dispersed silicates and phosphates. Especially preferred polymers
for adjusting the viscosity or generally the consistency of the
first paste are biocompatible water-soluble polymers such as
soluble starch and starch derivatives, cellulose derivatives,
collagen, gelatin, PEG or PEO (polyethylene oxide),
PEG-PPG-copolymers, water soluble modified
polyacrylates/polymethacrylates, PVP, PVA etc.
[0053] in particular in the case of water-based polymer pastes the
addition of suitable surface-active substances is advantageous.
[0054] Further additives of the first component depend on the
desired field of application and comprise in particular the x-ray
contrast agents disclosed for bone cements, antibiotics, other
active ingredients, coloring agents, and filler materials.
[0055] The second component is comprised in a simple case of the
(bone cement) monomer as a reactive organic liquid, a co-starter or
initiator and an inhibitor for preventing premature polymerization.
The co-starter can optionally also be provided in the first
component. Since in the context of the present invention any liquid
suitable for polymerization is suitable as a reactive organic
liquid, substances are also included that are already used
presently in two-paste systems (e.g. dental filler materials),
i.e., usually multi-valent macromers such as bis-GMA and (di-,
tri-, . . . , poly-) ethylene glycol dimethacrylate, multi-branched
PEG-n-(meth-)acrylates and analog acrylates and methacrylates and
their mixtures. These macromers have already a relatively high
viscosity or can be adjusted by targeted mixing of the macromers to
the desired viscosity. Further adjusting possibilities result by
mixing with inorganic and organic fillers as they are known from
the technology of dental molding and filling materials. For the
application as bone cements, as fillers in particular those with
bioactive properties are suitable, i.e., in particular calcium
and/or phosphate-containing compounds.
[0056] In view of the preferred use of the materials according to
the invention as bone cement the second component contains
preferably the low-molecular monomer methyl methacrylate (MMA).
Since MMA has a very low viscosity, a preferred embodiment of the
invention resides in that the second paste contains a polymer
dissolved in MMA and, by means of the type and quantity of
dissolved polymer, the viscosity of the second paste is adjusted to
the desired values. Even though basically all polymers soluble in
MMA are conceivable, those of the type of polyacrylic acid ester,
poly methacrylic acid ester, polystyrene, and their copolymers are
preferred. Especially preferred are the polymers, respectively,
that in a two-paste system are substantially the same as (or
identical to) the respective chemical composition of the dispersed
polymers of the first paste and--if at all--differ only in regard
to the copolymer contents and/or molecular weight.
[0057] The second component of the polymer system can also be
present as a paste but also as a liquid (solution) with a viscosity
of preferably <200 Pa*s.
[0058] According to a preferred embodiment of the invention, the
starter--possible is also to provide starter and co-starter
together--is also in a form in the carrier liquid in which it is
stable. Typically, it is present as a dispersion in the carrier
liquid or it is contained in the dispersed polymer. The radical
starter BPO that is contained in all commercially available bone
cements is employed in these two forms and the technology according
to the invention in both cases can be realized in the same way. The
stability of the radical starter--such as BPO--in aqueous
dispersion is technologically a great advantage relative to known
two-paste systems that work with dissolved BPO because BPO, like
other conventional peroxides in dissolved form, has the tendency to
spontaneously decompose and is therefore only storage-stable to a
limited extent. Corresponding bone cements such as Cortoss.RTM. by
Orthovita must therefore be stored with cooling in order to limit
the premature decomposition of BPO. In the present invention,
preferably an aqueous solution as a carrier liquid is employed and
dispersed BPO is storage-stable therein to an unlimited extent. The
same holds true also for other relevant peroxides.
[0059] According to an advantageous embodiment according to claim 6
the components of the polymer system contain a starter system of a
two-component radical starter with a starter component and a
co-starter, polymerization accelerator or initiator as a second
radical starter component. In this connection, the starter
component is present in the first component of the polymer system
in undissolved form and the second radical starter component is
contained in the second component of the polymer system.
[0060] Preferably, the starter component is a peroxide and the
second radical starter component is a tertiary amine. The
respective components of the starter system are substantially
stable and storable in the respective component of the polymer
system at normal conditions until components are mixed.
[0061] Inasmuch as the polymer system requires for reaction a
co-starter or initiator, the co-starter or initiator is present
preferably in dissolved form in the second component but can also
be a suspended or dissolved component of the first component
inasmuch as both components of the starter system in the carrier
liquid of the first component of the polymer system cannot react
with one another because e.g. one or both components of the starter
system are insoluble in the carrier liquid. As a co-starter
tertiary amines are preferred as they are used currently in
commercially available bone cements. Basically, all co-starters are
however suitable in this context which are practical in medical and
technical polymerizations systems. The selection of the starter
system depends on the application purpose of the polymer system
according to the invention.
[0062] The polymer system according to the invention contains the
starter in finely divided form in the carrier liquid (wherein it
can be present in freely dispersed form as well contained in the
polymer or adsorbed to the polymer surface). Additionally, also the
co-starter can already be contained in the carrier liquid inasmuch
as it is ensured that both substances, e.g., because of lack of
solubility in the carrier liquid, are stable in this environment
and neither decompose prematurely nor react with one another. In
the polymer system according to the invention both components and
the starter components contained therein therefore are stable until
they are mixed with one another. This holds true also for
conventional two-paste polymer systems; however here only the
reaction speed of the starter is lowered in order to achieve by a
precisely matched ratio of starter to inhibitor (in combination
with storage under cooling) an acceptable storage capability for
practical use. An important aspect of the present invention is
therefore that the starter is dispersed in a carrier medium
(carrier liquid of the first component) in which it is
storage-stable to a satisfactory degree. Upon mixing first and
second components a transfer of the starter from the first into the
second component takes place with dissolving of the starter
component. As soon as the starter is dissolved in the second
component of the polymer systems, it reacts spontaneously with the
co-starter (if required) and initiates the polymerization of the
monomer or macromer. According to the present invention the
employed starter is thus insoluble in the first component and
soluble in the second component and mixing of both pastes leads to
dissolving of the starter and co-starter in the same phase so that
both substances can react with one another (if dissolving of the
starter in the reactive monomer solution alone does not lead to a
satisfactory reactivity).
[0063] The implant material according to the invention of two
components can be formulated such that the carrier liquid of the
first component and the monomer solution of the second component
are partially or completely dissolvable in one another so that both
liquids form solutions or mixtures in the chemical sense. This is,
for example, the case when organic liquids such as propane diol are
used as carrier liquid for the first paste and the monomer solution
of the second paste is based on MMA. Advantages in this embodiment
primarily are based on a different mechanical behavior because in
this case a homogenous matrix is formed and no pore system. Another
important aspect is present when the inventive implant material is
to be used as an active ingredient carrier. In this case, by means
of such a dense matrix that in regard to its density can be very
well adjusted the active ingredient release can be matched to the
requirements within wide ranges.
[0064] A particularly preferred embodiment of the invention resides
in that the carrier liquid of the first component and the monomer
solution of the second component in the chemical sense are not
miscible and/or not soluble or only minimally soluble in one
another and that therefore upon mixing of the components
substantially a physical mixture with formation of at least two
separate phases results. This situation is particularly present and
in particular preferred when the carrier liquid of the first
component is an aqueous solution and when the second component is
based on a monomer solution wherein the employed monomers have a
minimal solubility in water. The latter is particularly present
when as a monomer MMA or other non-polar esters of acrylic acid or
methacrylic acid (e.g. butyl methacrylate) or styrene or their
mixtures are used. In this connection it is expressly underscored
that the non-miscibility or minimal solubility is related only to
the carrier liquid and the monomer liquids and that the substances
that are dissolved in both liquids or in particular suspended
therein can still dissolve in the other liquid, respectively.
[0065] The polymer system according to the present invention
contains in general one or several substances that are present in
suspended form in the respective carrier liquids and whose surface
properties may counteract a stable dispersion. This is true, for
example, for non-polar polymer powders that are suspended in
aqueous solution or polar substances that are suspended in the
monomer liquid. It is therefore an aspect of the invention that
these dispersions by suitable surface-active substances are
enhanced and stabilized. In the case of the application as a bone
cement or generally as an implant material biocompatible
surface-active agents are used for this purpose and in particular
those that are approved and/or successful as pharmaceutical
adjuvants.
[0066] Moreover, a preferred aspect of the present invention is the
targeted addition of surface-active substances to one or both (or
all) components of the polymer system according to the invention
which in case of components whose liquids are not miscible in the
chemical sense with one another or only have a minimal solubility
in one another, assist in the formation of a physical mixture of
the two pastes and stabilize this mixtures at least until
polymerization has advanced to such an extent that no longer a
significant or disadvantageous separation of the components can
occur. As surface-active substances in principle all substances are
to be taken into consideration that for the respective application
of the polymer system according to the present invention are
suitable and approved, in particular--in the case of use as implant
material--all biocompatible surfactants that are currently also
employed already in pharmaceuticals, cosmetics, foodstuffs or
medical products and/or are approved for such applications. For
technical applications the same holds true.
[0067] It is known in pharmaceutical technology and in cosmetics
that in many cases the combination of several surfactants for
obtaining the desired effect are required or that by combination of
different surface-active agents effects can be achieved that cannot
be realized with a single substance. It is therefore a preferred
aspect of the present invention that at least one or all components
of the polymer system contain at least one biocompatible
surface-active agent that assists in the formation of a physical
mixture of the components.
[0068] Preferred among the plurality of possible surfactant
additives are primarily biocompatible anionic and non-ionic
surface-active agents. On the one hand, these two groups in
principle are considered to be better compatible and, on the other
hand, they encompass almost any number of homologue derivatives
with which a targeted adjustment of property spectra is possible.
Especially preferred in case of implant materials are formulations
in which at least one component contains a bio-compatible anionic
surface-active agent that contains at least one carboxyl group,
sulfate group or phosphate group because these surface-active
agents at the same time may serve as crystallization seeds for bone
minerals.
[0069] Also particularly preferred is the use of anionic
surface-active agents of the type of soap, i.e., fatty acids and
their alkali salts or alkaline earth salts. Among these, especially
preferred is the use of oleic acid and its sodium, potassium,
ammonium, calcium, zinc and magnesium salts.
[0070] Especially preferred are furthermore formulations that
contain more than one surface-active agent wherein at least one of
the surface-active agents is anionic and at least one second
surface-active agent is non-ionic. In this context, also such
surface-active substances are to be understood as a non-ionic
surface-active agent that in the technological terminology are
referred to as co-surfactants and, for example, comprise aliphatic
alcohols. Especially preferred are those surface-active agent
combinations which assist the components of the polymer system
according to the invention to form (spontaneously) microemulsions
upon mixing. Microemulsions have the great advantage that they can
form spontaneously, have a reproducible structure, and are
thermodynamically stable. Their formation therefore leads to a
particularly homogenous matrix of the polymerized monomer
solution.
[0071] According to a preferred embodiment of the invention at
least one component of the polymer system contains at least one
biocompatible non-ionic surface-active agent of the group of
polyoxyethylene fatty alcohol ethers (Brij types), polyoxyethylene
sorbitan fatty acid esters (Tween types), alkyl aryl polyether
alcohols (Triton types), polyoxyethylene polyoxypropylene polymers
(random or block; Pluronic types). According to a further preferred
embodiment at least one component of the polymer system contains at
least one biocompatible anionic surface-active agent of the group
of fatty alcohol sulfates, fatty alcohol sulfonates, their
ethoxylates, their respective alkali salts, the group of fatty
alcohol phosphates (amphisol types), fatty alcohol phosphonates,
their ethoxylates and/or their alkali salts.
[0072] According to claim 13, in a further embodiment of the
invention the carrier liquid or the monomer solution contains
water-soluble monomers or macromers that during or after
polymerization of polymer system are also polymerized. These
water-soluble monomers or macromers polymerize preferably at the
boundary surface to the polymer matrix or directly in the aqueous
solution. They generate thus in the aqueous phase a hydrogel that
either is deposited on the polymer matrix or that fills the aqueous
phase more or less homogeneously. In this way, composition,
diffusion behavior, swelling behavior etc. of the aqueous phase can
be affected additionally. Examples of suitable water-soluble
monomers are methacrylic acid, HEMA, HPMA, HEMA phosphate,
sulfopropyl methacrylate, their homologues, and their mixtures.
Examples of water-soluble macromers are PEG-mono-methacrylate,
PEG-di-methacrylate, branched PEG-n-methacrylates, their homologues
and their mixtures. These listings have only exemplary character;
comprised are all polymerizable water-soluble monomers whose
polymerization may result in hydrogels.
[0073] The quality of the implant material according to the
invention depends in special applications quite fundamentally on
the fine adjustment of the two components. The embodiments show
that with relatively simple polymer systems already very good
results can be obtained. However, the requirements in regard to the
polymer system depending on the field of application can be very
different. As already mentioned above, it may be expedient to
provide a polymer systems that form a pore system by phase
separation or immiscibility of two phases. As a bone implant it can
be desirable furthermore that such a pore system largely or
completely is interconnected so that the surrounding bone can grow
in. This object places great demands on the composition of the two
components so that by means of viscosity, structural viscosity,
surface-active substances, particle size of the suspended polymers,
and auxiliary agents and polarity of liquids the formation of the
pore system can be controlled. Methods and auxiliary substances for
a targeted manipulation of the behavior of powder/liquid mixtures
and emulsions are primarily known from pharmaceutical technology
and cosmetics. In the present invention these technologies are used
for the first time in order to realize a novel implant material.
Especially claimed are therefore embodiments of the polymer systems
according to the invention in which the respective components are
adjusted with respect to their viscosity by polymers contained and
dissolved therein or finely divided suspended organic, inorganic or
organo-mineral components and by means of which mixing and
separating behavior before and during polymerization can be
affected. Such substances are, for example, water-soluble polymers
such as soluble starch and starch derivatives, cellulose
derivatives, collagen, gelatin, PEG, PEG-PPG copolymers,
water-soluble modified polyacrylates/polymethacrylates, PVP, PVA
etc. that may be present dissolved in the aqueous phase as well as
dissolved in the organic phase (monomer) or suspended. For
adjusting the viscosity of the organic phase all polymers are
suitable that are soluble in the respective monomer solution and
that are compatible with the polymer components. This holds true in
particular for the respectively selected polymers of the first
component which however may differ from the employed particulate
polymers in particular with respect to molecular weight. These
polymers can also be used directly as a solution in the monomer or
as a particularly finely dispersed powder in the water-based first
component so that these particularly finely dispersed particles in
contact with the monomer solution will dissolve very quickly and
effect a fast viscosity increase in the monomer solution. In
addition to the dissolved or soluble substances, additives are
conceivable that in both components or phases are insoluble and
that primarily affect the structural viscosity of the components or
stabilize the phase boundaries, such as finely divided silicates
and phosphates that optionally can be modified additionally.
[0074] An important aspect of the present invention is the
excellent miscibility and the minimally invasive administration of
the two components of the polymer system. Tests have shown that for
manual mixing, in particular however mixing in a two-chamber system
and static mixers, the viscosity of the two components during
mixing may not be too high and advantageously should further
increase significantly only after the mixing step. The viscosity of
the components of the polymer system (before mixing) is therefore
advantageously at a value of <200 Pa*s. At higher viscosities a
thorough mixing of the components is made more difficult or
extrusion by a static mixer is impaired.
[0075] In particular in case of use of the polymer system according
to the invention as bone implant materials microcrystalline,
nanocrystalline or amorphous calcium phosphates are preferably used
as mineral additives. They can have, on the one hand, the function,
as mentioned above, to modify the viscosity of the pastes and/or to
stabilize the phrase boundaries between the aqueous phase and the
organic phase. Moreover, they can have additionally or primarily a
biological function in that they increase the bioactivity of the
implant material and advance growing of bone into an optionally
present pore system.
[0076] The bioactivity of the polymer system according to the
invention as an implant material for applications in the bone area
is advanced particular preferred in that at least one of the
components contains substances which after introduction of the
material at an implant site enhance the mineralization of the
surface of the implant material. Methods for bioactivation of bone
cements are disclosed in DE 10 2005 023 094 A1.
[0077] A preferred variant resides in that the polymers suspended
in the first component of the polymer system are comprised entirely
or partially of copolymers that contain anionic groups or can
dissociate or hydrolyze to form such groups.
[0078] Especially preferred are those copolymers that contain
phosphate, carboxyl, sulfate, or silicate groups. Also particularly
preferred are compositions that aside from such anionic copolymers
contain calcium salts and/or buffer substances that have a high
buffering capacity in the alkaline range. The calcium salts and the
buffering substances may be contained in any of the components.
Especially preferred are also compositions that contain anionic
monomers in the second component of the polymer system and/or in
which anionic copolymers are dissolved or suspended in the second
component of the polymer system.
[0079] The method described in DE 10 2005 023 094 A1 is used in the
present case for the first time on the implant material according
to the invention and has in this case the special effect that the
bone not only can grow in on the surface of the implanted bone
cement but also can grow into a pore system that is being formed.
It is therefore particularly preferred that the polymer systems
according to the invention--inasmuch as they are to be used as bone
implant material--contain substances e.g. ethylene glycol
methacrylate phosphate or methacrylic acid that may serve a
mineralization seeds for deposition of bone-analogue minerals. In
addition to the mineralization seeds themselves at least one
component may contain additives in particular soluble calcium salts
and buffering substances that may advance mineralization. The
buffering substances are able to adjust or keep in the direct
vicinity of the implant material the pH value in the adjoining
aqueous medium at a neutral to alkaline range, preferably pH 7.4 or
above.
[0080] Advantageously, at least one component contains at least one
biocompatible substance that under biological conditions and in
particular under conditions as they are present in the bone serve
as crystallization seeds for mineral depositions and/or advance the
formation of such mineral depositions. In particular polymer
substances are provided for this purpose with at least one
carboxyl, sulfate and/or phosphate group or a siloxane group as a
substituent.
[0081] The implant material according to the present invention and
the method for producing bone implant materials comprised thereof
enable a targeted influence on the components of the phases that
are being formed. In particular, during the course of mixing of the
two components and the subsequent polymerization two phases can be
formed whose composition can be controlled in a targeted fashion.
The water-based phase can be understood as a pore system within the
continuous polymerized organic phase wherein, with appropriate
selection of the composition of the polymer system and the
processing parameters, the water-based phase can also form a
continuum and thus form an interconnected pore system. For the
biological behavior the composition of the water-based phase is of
particular importance. In addition to the essential components of
the aqueous solution that serves as a carrier liquid of the polymer
suspension of the first component, it can contain various auxiliary
agents and active ingredients which, on the one hand, affect the
cell activity in the surrounding tissue and, on the other hand, can
contain active ingredients that are to be released from this pore
system into the surroundings of the implant material and whose
release kinetics can be effectively controlled by means of the
auxiliary agents contained in the aqueous phase. An important
example in this connection is the combination of a large proportion
of the conventional bone cements with antibiotics that, as
mentioned above, are released only very slowly and in very minimal
quantity from the cement matrix. In the case of the inventive
polymer system, the antibiotics (and/or other suitable agents) can
be added to one or both pastes depending on whether a quick or slow
release is desired (as a result of the large surface area the
release action in any case will be much faster than in all
conventional bone cements). The predominantly relevant
water-soluble active ingredients--such as antibiotics--are
preferably added to the first water-based paste and after
polymerization of the implant material are practically exclusively
present in the aqueous solution that fills the pore system. When
the pore system is substantially interconnected, the active
ingredients can be released quickly by diffusion out of the pore
system. In this way, the active ingredients can be added to the
bone cement in much lower dosage in comparison to dosage used
currently in conventional bone cements. In addition, the risk of
developing resistance as a result of sub-inhibitory antibiotic
concentrations is eliminated, which risk, in the case of
conventional antibiotic-containing bone cements, has not yet been
eliminated and represents a significant approval hurdle.
[0082] The release of the active ingredients can moreover be
controlled in wide ranges in that by selection of suitable salts
the solubility of the active ingredients can be affected, e.g., the
solubility of cationic antibiotics that are primarily used in bone
cements, such as amino glycosides (gentamycin, tobramycin) and
glycopeptides (vancomycin), can be reduced significantly by
lipophilic and amphiphilic anions and a prolonged release can be
achieved in this way. A further very effective control of the
release results by use of auxiliary agents in the aqueous phase
that impair free diffusion of dissolved active ingredients, i.e.
practically plug the pore system. These agents can be in particular
the same auxiliary agents that as water-soluble polymers such as
soluble starch and starch derivatives, cellulose derivatives,
collagen, gelatin, PEG, PEG-PPG copolymers, water-soluble modified
polyacrylates/polymethacrylates, PVP, PVA, etc., effect the
viscosity of the aqueous phase but also particulate and optionally
swellable substances such as starch derivatives, insoluble
collagen, gelatin (insoluble) or mineral particles such as
silicates or calcium phosphates that also can adsorb and release
with delay optionally added active ingredients.
[0083] Especially preferred are components that form a pore system
that is interconnected predominantly or completely. This provides
decisive advantages for the biological behavior in that the
surrounding tissue thus has the possibility to grow deeply into the
pore system. Further advantages result in connection with the
active ingredient release. In certain applications and in certain
formulations--that are not limited to the use as implant
materials--there result also biochemical or technological
advantages. Biochemical advantages are provided inasmuch as an
interconnected pore system can function in an elastic polymer
matrix as an effective hydrodynamic system that reacts in a damping
fashion in that the liquid is forced out of the pore system and
flows back upon load relief. In comparison to materials available
up to now, such a material can better mimic in the bone area
primarily the biomechanical function of the spongy bone of the
joint-near areas and of the spine.
[0084] The formation of a pore system in the implant material
according to the invention occurs automatically when as a carrier
liquid for the first component a substance is used which is not
miscible with the monomer liquid. In many applications the
minimization of porosity is desirable for mechanical reasons as is
attempted also in conventional bone cements. Especially in the
field of application of osteoporotic bone however also a reduced
stiffness of bone cement is desirable for biomechanical reasons.
For such applications formulations with an increased porosity are
desired. Examinations have shown that in particular for higher
porosities the compression strength of the samples is significantly
reduced but is still at a level that in particular for filling
osteoporotic bone is viewed to be particularly beneficial (see:
Boger A., Verrier S., Bohner M., Heini P., Schneider
E.--Injizierbarer poroser Knochenzement fur die Vertebroplastik mit
physiologisch angepassten mechanischen Eigenschaften (Injectable
porous bone cement for vertebroplastics with physiologically
matched mechanical properties), Bern; DGU, 2005). The examples show
also that the goals mentioned in the cited work can be achieved
with the implant material according to the invention in an
excellent and reliable way. Preferred are therefore compositions of
the implant material according to the invention that result in a
porosity (i.e., they thus comprise immiscible combinations of
carrier liquid and monomer liquid). Particularly preferred are
compositions that result in a porosity of >10 percent by volume
in the cured implant material and especially preferred are
compositions that result in a porosity of >15 percent by
volume.
[0085] The combination of implant materials according to the
invention with pharmacologically active ingredients or other
substances that serve an additional function has already been
explained at various locations. At this point this claim will be
summarized and particularly underscored because of its relevance
for the present invention. Claimed are all active ingredients that
are essential for the function of the polymer system according to
the invention, that may assist in its intended application as a
medical product or technical product or may expand its use to
further fields of applications. The already mentioned and the
following examples are not to be understood in any way as
limiting.
[0086] For the use of the implant materials according to the
invention as bone implant materials, the combination with
substances that generally facilitate imaging diagnostics or make it
possible at all is of particular importance. These substances
include the classic x-ray contrast agent of bone cements
(BaSO.sub.4, ZrO.sub.2) as well as often experimentally employed
metal powders (Ta, W, Fe, Co or alloys of these elements).
Furthermore, the combination with non-ionic x-ray contrast
materials (usually organic iodine compounds) or the use of
iodine-containing monomers or polymers is included as well as
diagnostic active ingredients that are important for imaging
methods other than x-ray (Tc, Gd).
[0087] Antimicrobial active ingredients have been established as an
additive to bone cements for many years--their advantageous use or
the advantages of the invention for the combination with active
ingredients for the local application are already apparent from the
discussions above. For the polymer system according to the
invention all combinations with microbial active ingredients are
claimed, in particular with antibiotics and their combinations,
antiseptic substances, antimicrobial peptides and proteins,
bacteriophages, salts--in particular of silver or bismuth, finest
divided metallic silver, and antimicrobially acting combinations of
these active ingredients with one another and other active
ingredients. Claimed is also the combination with
anti-proliferative, cytostatic, immunosuppressive or
anti-inflammatory substances.
[0088] Especially preferred is moreover the combination with active
ingredients that can affect specifically or non-specifically the
bone metabolism. These include many vitamins, in particular vitamin
D, moreover substances that have an inhibiting action on
osteoclasts and in general on inflammation cells or inhibit
specific metabolism reactions of the osteoclasts and inflammation
cells such as in particular their production and secretion of acid
(for example, proton pump inhibitors, bisphosphonates). In
particular included are also active ingredients that stimulate a
differentiation of osteoblasts from precursor cells such as the
growth factors of the TGF.beta. family, in particular BMP 2 and BMP
7, other growth and differentiation factors as well as active
ingredients that generally may increase locally the metabolism
performance (such as PTH, PTH fragments, IGF, and other anabolic
hormones) and those that enhance the formation of blood vessels in
the implant surroundings (such as FGF or VEGF).
[0089] Many of the aforementioned active ingredients--and
additional ones relevant for the bone--are not combinable in a
meaningful way in prior art bone cements because they cannot
withstand the polymerization conditions, may not be released or not
released in a sufficient quantity, have risky long-term effects or,
because the predominant part of active ingredient is not released,
are not suitable for economic reasons for combining with
conventional bone cement. Many of these active ingredients are
combinable for the first time in combination with the polymer
system according to the invention in a pharmacologically expedient
way with an implant material and/or a bone cement.
[0090] The implant materials according to the invention can be
produced in a simple way. The mixing step is already possible in a
simple mixing cup with excellent results. In the context of a
simple mixing action and reproducible quality of the mixing result,
the processing of the polymer system in a pre-filled and
pre-packaged container and mixing system is a particularly
preferred administration form. In this connection, there is also a
great advantage relative to conventional bone cements that cannot
be processed in such simple mixing systems that are usually
embodied as double-chamber syringes. Suitable double-chamber
syringes for the polymer system according to the invention are
obtainable e.g. from the company Mixpac.RTM.. The claim is however
not limited to these brands but also encompasses all systems,
including those that are mechanically driven and e.g. customarily
employed by dentists or dental technicians and are used in this
connection for mixing highly viscous pastes (e.g. for impression
materials). The customary mixing ratios range from 1:1 through 1:2,
1:4 to 1:10, but can also be adjusted to other ratios. For the
polymer systems according to the invention mixing ratios of
1:1,1:2, and 1:4 are in particular suitable and preferred.
[0091] The field of bone implant materials is a preferred field of
application of the implant materials according to the invention in
which the principal advantages of the implant material according to
the invention are particularly apparent and particularly
pronounced. As already mentioned before, the conventional bone
cements, despite their wide use, have severe weaknesses in some
aspects that can be at least partially overcome with the polymer
systems according to the invention. They will be summarized briefly
in the following: [0092] In contrast to the complex mixing of
powders in conventional bone cements the pastes can be prepared in
a simple way and in inexpensive machines (e.g. planetary mixer).
The risk of separation of powders of different density and grain
size is not present. The pastes can be mixed with one another
without problem without the risk of admixture of air bubbles. No
macro defects result which in conventional bone cements present a
significant problem for the mechanical performance. [0093] The
shrinkage that is known from conventional bone cements and that is
particularly disadvantageous occurs for the bone cements according
to the present invention to a significantly reduced extent and,
depending on the formulation, can be almost completely suppressed.
Since in conventional bone cements the shrinkage is a function of
the monomer contents and the polymer system according to the
invention employs a much reduced amount of monomers, the shrinkage
is in this case also significantly lower. [0094] Like shrinkage the
exothermicity is also a function of the monomer contents and
accordingly it is also reduced in the same way. Moreover, in the
water-based pastes the introduced water enhances with its high heat
capacity as an effective means the temperature increase during
polymerization to an acceptable level. [0095] The polymer systems
according to the invention in many cases do not achieve the
absolute mechanical values of the conventional bone cements for
compression strength and bending strength but they are in many
cases (depending on the formulation) above the standard values. On
the other hand, the polymer systems according to the present
invention have such a mechanical behavior--and for this reason they
are primarily proposed herein--that they are predestined in
particular for filling spongy bone defects. In particular, their
stiffness is significantly reduced so that as an implant they will
damage the adjoining bone to a lesser degree. Moreover, special
formulations exhibit pronounced damping properties. Surprisingly,
however some of the tested formulation also have static strength
values which are comparable to those of the best conventional bone
cements. Applicability for fixation of joint implants is thus also
provided. [0096] The superior release of active ingredients has
already been mentioned in detail. [0097] The bioactivity is
superior in the polymer systems according to the present invention
with respect to several aspects. On the one hand, by the variety of
combination possibilities with bioactive ingredients, secondly by
the reduced hardness that enhances biomechanical induction of bone
healing, thirdly by the possible introduction of bioactive minerals
and combination with mineralization seeds, and fourthly by the
possible realization of an interconnected pore system that enables
growing in of bone and blood vessels deeply into the cement
matrix.
[0098] As a result of these advantages, the use of the polymer
systems according to the invention for producing bone replacement
material, bone cements, bone adhesives, and implantable active
ingredient carriers is particularly preferred. Bone cements are
configured in accordance with the implant material of the present
invention and are matched to the specific applications. Bone
replacement materials are formulations based on the implant
material according to the invention, for example, for filling bone
defects. In this case, it can be advantageous that the bone
replacement material is shaped in the form of a cured solid
workpiece from the implant material according to the present
invention before implantation into the body and subsequently is
introduced/implanted into the bone defect.
[0099] Bone adhesives are formulations of the implant material
according to the present invention, for example, for bonding and
securing bone fragments after bone fractures or for attachment of,
for example, metallic or ceramic or other polymer implant materials
on or in the bone. In this function, the bone adhesives contain in
addition to the implant material according to the invention
adhesion-enhancing substances that are known from the dental field
as adhesion promoters and/or substances such as polyacrylate,
anionic monomers, and polymers and/or copolymers produced
therefrom. These substances are used in the dental field inter alia
for improvement of depletion of filler materials on the tooth
substance (which is very similar to bone substance). They are
combinable particularly advantageously and versatilely with the
implant material according to the invention because they can be
combined with the first component of the polymers system as well as
with the second component of the polymer system in wide
concentration ranges. This differentiates the implant materials
according to the invention from conventional formulations because
the charged or strongly polar adhesion promoters that in this
respect are particularly effective have no or only minimal
solubility in conventional bone cements (or their monomer
solutions). Particular preferred is the combination with
polyacrylic add, copolymers of acrylic acid and/or methacrylic
acid, in particular copolymers with maleic acid and their salts.
Also particularly preferred in this respect are combinations with
phosphate group-containing (ethylene-unsaturated) monomers and/or
polymers or copolymers produced therefrom. Especially preferred are
admixtures of the aforementioned adhesion promoters in a
concentration of 0.1 to 50% relative to the total weight of the
implant material. The addition of adhesion promoters effects a
stronger adhesion of the implant material on the bone tissue.
[0100] Active ingredient carriers are formulations of implant
materials according to the invention that contain pharmacologically
active ingredients in concentrations that effect a therapeutic
function in the human or animal organism. These active ingredients
are released from the implant material after implantation.
Preferred is therefore the combination with active ingredients that
develop a direct local action and thus directly act on the tissue
in the surroundings of the implant material. Preferred is the
combination with active ingredients that stimulate the bone
metabolism and counteract local inflammations. Especially preferred
are active ingredient carriers on the basis of the implant
materials according to the invention that contain antimicrobial
active ingredients such as antibiotics.
[0101] An especially preferred application of the polymer systems
according to the invention is the filling of bone defects and the
augmentation of osteoporotic bone. In the predominant number of
cases this application is done by minimally invasive operation
technique.
[0102] A typical example for this are the various methods of
vertebroplastics which in recent years have become more and more
popular and whose clinical effectiveness has been documented
increasingly better. It is therefore to be assumed that these
treatment techniques will be further developed and the number of
treated cases will increase significantly. The further development
of methods of vertebroplastics (including the so-called
kyphoplastics) are particularly dependent on the availability of
improved augmentation materials. The currently available bone
cements are only suitable to a limited extent; even though some
products are offered specifically for vertebroplastics they are
still only conventional bone cements with slightly modified
viscosity, curing kinetics and increased contents of x-ray contrast
material. The polymer systems according to the invention are
superior in principle in these applications because they are much
simpler with regard to handling, exhibit reduced shrinkage, reduced
heat development, higher bioactivity and improved biomechanical
compatibility with the bone.
[0103] For clinically successful application they must be combined
with suitable application systems for introduction of the polymer
system into the bone. For this purpose, in the simplest case simple
syringe systems can be employed as they are used today in
connection with vertebroplastics. Expedient is however a mixing
action of the polymer system in a double chamber syringe and a
static mixer and the combination with an injection cannula or a
suitable tube that extends to the site of implantation.
Advantageous is in particular that the polymer system is mixed only
upon extrusion i.e., in a simple way by means of a cement cartridge
several injections can be made and no temporally matched
preparation is required because the polymer system is dispensed
already application-ready from the syringe.
[0104] An especially preferred application is the method known as
kyphoplastics in which first the osteoporotic bone of the vertebra
body is expanded by a balloon and compressed in the surroundings
and subsequently a bone cement is applied into the produced cavity.
Especially in this application the combination of the application
instrumentation with the polymer system according to the invention
is particularly advantageous because in this case an advantageous
application system can be combined with an advantageous filler
material. Therefore, all combinations of the polymer system
according to the invention with application systems are claimed
that are suitable to introduce in a minimally invasive way the
polymer system according to the invention into bone defects,
fracture gaps, osteoporotic bone, bone tumors or bone structures
that in any other way are rarefied. Also, all attachments are
claimed that can be attached to a mixing system of the type of the
aforementioned double chamber syringes or can be connected with
such a system for the purpose of applying with their aid the
polymer system according to the invention to the target
location.
[0105] The implant materials according to the invention can be
handled in a particularly advantageous way intraoperatively i.e.,
can be prepared for the introduction into the body. This
differentiates them fundamentally from conventional bone cements
that are mixed from powder and liquid. At the same time, the
material properties enable the simple and reliable minimally
invasive application by means of a cannula. The free combinability
of the first and the second components of the polymer system in a
very broad mixing ratio (e.g. 1:1, 1:2, 1:4) enables also the use
of the compositions according to the invention for the production
of bone adhesives, bone replacement materials, and implantable
active ingredient carriers in addition to the application as bone
cements.
[0106] Based on the following examples the invention will be
explained in more detail.
EXAMPLE 1
[0107] Example for the principal composition of the polymer system
according to the invention: [0108] a) component 1: 30 g polymer
powder Degacryl.RTM. 6658 F (copolymer of PMMA and PMA (94:6)
containing 1.5% BPO, particle size approximately 45 .mu.m); 15 ml
water (demineralized); 0.45 g surface-active agent (Tween 80); 0.3
g carboxymethyl starch (type PO); [0109] b) component 2: 10 ml
methylmethacrylate (MMA) containing 0.5% DMPT.
[0110] Example 1 shows in a simple experiment the functional
principle of the polymer system according to the invention. As a
first component a commercially available polymer known from dental
technology and supplied by the company Degussa (Degacryl.RTM. 6658
F) is used. This polymer is mixed with the aqueous solution of a
surface-active agent--for improved miscibility of the polymer
powder with the aqueous solution and subsequent mixture of the
paste with the monomer liquid--and a polymer (carboxymethyl
starch)--for increasing the viscosity--to a macroscopic homogenous
paste. The thus obtained paste shows excellent storage properties
in that it exhibits no noticeable changes after storage in a closed
glass vessel under normal conditions for two months. The second
component is comprised in this example of conventional bone cement
monomer. The starter system is comprised of BPO/DMPT and is
distributed, as in conventional bone cement, onto both
components.
[0111] Mixing of the components 1 and 2 is realized in a mixing cup
with a spatula. After a mixing duration of one minute a homogenous
mixture is obtained which in approximately five minutes cures with
heat development. Cylindrical shaped bodies of this mixture with
dimensions of 10 mm diameter and 20 mm height achieve after
incubation over night in simulated bone liquid at 37.degree. C. a
compression strength of 35-50 MPa.
[0112] The results showed that upon mixing of the water-based paste
of polymer powder with a monomer liquid that are derived each of
the composition of conventional bone cements, a polymerization
reaction is initiated that allows the conclusion that the polymer
powder suspended in water bonds with the monomer solution, that the
polymer powder partially is solubilized or dissolved, that the BPO
contained in the polymer powder is extracted from it and is
dissolved in the monomer, that in the monomer solution by the
encounter of the two starter components a polymerization reaction
is initiated, and that by polymerization an intimate bonding
between polymer powder and polymerized monomer is formed. The
obtained solid achieves a high compression strength that is less
than that of conventional bone cements but in this connection it
must be taken into account that the obtained solid has a porosity
of >30.% (see also example 3).
[0113] Surprisingly, the described formulation cures significantly
faster than a comparable formulation of powdery Degacryl.RTM. 6658
F that is mixed with the same monomer and requires approximately 12
minutes until cured.
EXAMPLE 2
[0114] Example for producing a bone cement according to the
invention on the basis of Palacos (Heraeus-Kulzer)
[0115] Component 1: 40 g powder of the bone cement Palacos.RTM. R
of the company Heraeus-Kulzer containing a mixture of PMMA/PMA
copolymers, x-ray contrast agent (zirconium dioxide), and benzoyl
peroxide (BPO) are mixed with 15 ml of an aqueous solution
containing 2.5% surface-active agent (Tween.RTM. 80) and 2%
carboxymethyl starch (type PO) to a paste. The paste is
macroscopically homogeneous and will not separate under normal
conditions.
[0116] Component 2: 10 ml methylmethacrylate (MMA) containing 0.5%
DMPT.
[0117] Mixing of components 1 and 2 in a mixing cup. After short
mixing duration with a spatula a homogeneous mixture is obtained
that cures in approximately five minutes with heat development.
Cylindrical shaped bodies of this mixture with the dimensions 10 mm
diameter and 20 mm height achieve after incubation over night in
simulated body liquid at 37.degree. C. a compression strength of
>50 MPa.
[0118] Example 2 shows that the results of example 1 can also be
transferred onto a formulation of a commercially available
conventional bone cement. Surprisingly, this formulation also cures
significantly faster than comparable formulation of the powdery
bone cement Palacos.RTM. that is mixed with the same monomer and
requires approximately 13 minutes until cured.
EXAMPLE 3
[0119] Implant material that after curing results in a solid with
interconnected pore system: [0120] a) component 1: 30 g polymer
powder Degacryl.RTM. 6658 F (copolymer of PMMA and PMA (94:6)
containing 1.5% BPO, particle size approximately 45 .mu.m); 15 ml
water (demineralized); 0.45 g surface-active agent (Tween 80); 0.3
g carboxymethyl starch (type PO). [0121] b) component 2: 7 ml
methylmethacrylate (MMA) containing 0.5% DMPT.
[0122] Mixing of components 1 and 2 is done in a mixing cup with a
spatula. After a mixing duration of one minute a homogeneous
mixture is obtained that cures in approximately five minutes with
heat development. Cylindrical shaped bodies of this mixture with
the dimensions 10 mm diameter and 20 mm height achieve after
incubation over night in simulated body liquid at 37.degree. C. a
compression strength of 30-40 MPa.
[0123] Spherical shaped bodies of this mixture of 20 mm diameter
after complete curing over night in simulated body liquid are dried
in a drying cabinet at 37.degree. C. and show a weight loss of
approximately 35% which corresponds to the calculated porosity.
After subsequent renewed incubation in simulated body liquid for 24
hours the shaped bodies absorb again the same amount of liquid.
This results prove the interconnected porosity. FIG. 1 shows in
this connection an image made by scanning electron microscope.
EXAMPLE 4
[0124] Application Kit
[0125] The application kit is comprised of a double chamber syringe
of the company Mixpac.RTM. and two components according to Example
1.
[0126] 20 ml of the component 1 according to example 1 is filled
into the larger chamber of a double chamber cartridge (4:1) of the
company Mixpac and is closed, free of air bubbles, with a plunger.
Subsequently, the smaller chamber is filled completely by means of
a syringe with a monomer, in which prior to this 5% of a PMMA
polymer (MW 230,000) has been dissolved homogeneously, after the
plunger has been moved to the same position as in the larger
chamber. The double chamber cartridge is subsequently closed off by
closure plug. For the purpose of mixing and dispensing the
cartridge is introduced into a dispensing device and the closure
plug is removed and exchanged for a static mixer. Subsequently, the
plungers of the chambers are uniformly forced by the dispensing
device forwardly and the paste as well as the monomer solution are
pressed through the static mixer whereby an intimate mixing is
performed. The first milliliter of extruded material is disposed of
as being insufficiently homogeneously mixed and the further
extruded material is homogeneously mixed and cures like the
manually mixed material in approximately 5 minutes. By means of the
double chamber syringe the material can be applied easily.
EXAMPLE 5
[0127] Implant material that after curing forms a solid with
interconnected pore system as a function of selected mixing ratios
of the first and second components of the polymer system and
preparation in a two-chamber mixing system. [0128] c) component 1:
20 g polymer powder Degacryl.RTM. 6658 F (copolymer of PMMA and PMA
(94:6) containing 1.5% BPO, particle size approximately 45 .mu.m);
5 g x-ray contrast agent (zirconium dioxide); 11 ml water
(demineralized) containing 2.5% surface-active agent (0.275 g Tween
80); 0.4 g polyethylene oxide (Polyox 574); 0.4 g sodium oleate;
0.5 g calcium chloride. [0129] d) component 2: methylmethacrylate
(MMA) containing 0.5% DMPT with 20% Degacryl M546 and 2%
emulsifying agent (oleic acid).
[0130] Mixing of the components 1 and 2 is done in a two chamber
mixing system wherein the indicated mixing ratio represents the
ratio of component 1 to component 2. Mixing and dispensing of the
components in the two chamber mixing system is realized as desired
by means of a dispenser or by means of a plunger by hand. By
ejecting the paste material through a static mixer a homogeneous
mixture is obtained that cures in approximately 5 minutes with heat
development. Cylindrical shaped bodies of this mixture with
dimensions of 6 mm diameter and 12 mm height achieve after
incubation over night in simulated body liquid at 37.degree. C. a
compression strength of approximately 30-50 MPa, depending on the
mixing ratio, respectively.
TABLE-US-00001 mixing system 4:1, mixing system 2:1, mixing system
1:1, dispenser dispenser manual plunger 10 ml double chamber 25 ml
double chamber 5 ml double chamber cartridge, mixing cartridge,
mixing cartridge, mixing attachment diameter 3.2 mm .times.
attachment diameter 4.2 mm .times. attachment diameter 2.5 mm
.times. length 16 mm length 12 mm length 16 mm compression
strength: compression strength: compression strength: 28.92 +/-
1.24 MPa 38.83 +/- 1.19 MPa 48.47 +/- 1.89 MPa porosity:
approximately porosity: approximately porosity: approximately 23%
19% 16% processing: processing: processing: excellent extrusion
excellent extrusion excellent extrusion behavior behavior behavior
complete cartridge complete cartridge complete cartridge emptying
possible emptying possible emptying possible homogeneously mixed
homogeneously mixed homogeneously mixed cement paste cement paste
cement paste paste viscosity paste viscosity paste viscosity
immediately after mixing: immediately after mixing: immediately
after mixing: .smallcircle. Legend redescription of paste
viscosity: paste viscosity : high viscosity of the cement mixture,
shape stability of the extruded cement mixture - bead of the cement
mixture remains shape after extrusion paste viscosity : average
viscosity of the cement mixture, bead current of the cement mixture
runs easily, bead shape still recognizable paste viscosity
.smallcircle.: minimal viscosity of the cement mixture, bead of the
cement mixture runs, individual beads combine
[0131] Mechanical parameters after a sample preparation in mixing
cup:
TABLE-US-00002 mixing ratio 4:1 mixing ratio 2:1 mixing ratio 1:1
compression strength: compression strength: compression strength:
34.17 +/- 1.55 MPa 47.17 +/- 4.84 MPa 53.78 +/- 3.26 MPa
[0132] Abbreviations:
[0133] bis-GMA bisphenol A dyglycidyl ether methacrylate
(bis-GMA)
[0134] BMP bone morphogenetic protein
[0135] BPO di-benzoyl peroxide
[0136] DMPT dimethyl-p-toluidine
[0137] DMSO dimethyl sulfoxide
[0138] FGF fibroblast growth factor
[0139] HEMA hydroxyethyl methacrylate
[0140] HPMA hydroxypropyl methacrylate
[0141] IGF insulin-like growth factor
[0142] MMA methylmethacrylate
[0143] PEG polyethylene glycol
[0144] PEO polyethylene oxide
[0145] PPG polypropylene glycol
[0146] PVA polyvinyl alcohol
[0147] PVP polyvinyl pyrrolidone
[0148] PMMA polymethylmethacrylate
[0149] PTH parathyroid hormone
[0150] TGF transforming growth factor
[0151] VEGF vascular endothelial growth factor
* * * * *